{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:18:34Z","timestamp":1792790314342,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,20]]},"group-title":"Neuroscience","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gilbert Family Foundation","id":[{"id":"https:\/\/ror.org\/01kf4yp82","id-type":"ROR","asserted-by":"crossref"}]},{"name":"MGB GCTI"},{"name":"National Institutes of Health","award":["RM1NS132996-01"],"award-info":[{"award-number":["RM1NS132996-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Familial Alzheimer\u2019s disease (fAD) is an early-onset form of AD caused by autosomal-dominant variants in APP, PSEN1, or PSEN2, with PSEN1 accounting for most genetically defined cases [1]. The hippocampus is among the earliest and most severely affected brain regions in AD [2,3]. Human induced pluripotent stem cell (iPSC)-derived brain organoids recapitulate key features of early human brain development and provide a tractable model for studying how fAD mutations perturb neurodevelopmental processes [4]. However, their interpretation is complicated by heterogeneous regional identity, variable maturation state, and cell-type composition across protocols [5,6]. Existing single-cell studies of human hippocampus cover prenatal [7] and postnatal [8\u201310] stages but do not provide a continuous developmental reference. By elevating the atlas approach in utilizing single-cell RNA-sequencing data, we obtain standardized information on the organoid cell class and type composition and maturation states.<\/jats:p>\n                <jats:p>\n                  Here, we constructed the Human Developing Hippocampus Atlas (HuDeHA), an integrated single-cell reference comprising 658,059 cells spanning post-conceptional week 3 to 15.3 years, and used it to benchmark iPSC-derived brain organoids carrying PSEN1\n                  <jats:sup>E280A<\/jats:sup>\n                  which is associated with fAD in a large Colombian population. Reference-based mapping revealed altered cellular composition in PSEN1\n                  <jats:sup>E280A<\/jats:sup>\n                  organoids, including reduced radial glia and increased neural crest-derived neurons. These changes were accompanied by cross-lineage transcriptional alterations, including broad upregulation of the ventral patterning factor MEIS2 and reduced expression of the A\u03b2-binding protein transthyretin (TTR) in choroid-plexus and ependymal-associated populations. Reconstructed neuronal-lineage trajectories showed a shift toward mature states in PSEN1\n                  <jats:sup>E280A<\/jats:sup>\n                  organoids. Together, these findings establish HuDeHA as a resource for developmental benchmarking of hippocampus-relevant organoid systems and describe cell-lineage-specific developmental changes in PSEN1\n                  <jats:sup>E280A<\/jats:sup>\n                  organoids that may inform interpretation of early cellular alterations in fAD.\n                <\/jats:p>","DOI":"10.64898\/2026.09.18.752796","type":"posted-content","created":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T10:05:10Z","timestamp":1789898710000},"source":"Crossref","is-referenced-by-count":0,"title":["A lifespan single-cell atlas of the human developing hippocampus benchmarks familial Alzheimer\u2019s disease brain organoids"],"prefix":"10.64898","author":[{"given":"Ekaterina","family":"Ivleva","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emil","family":"Kriukov","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph F.","family":"Arboleda-Velasquez","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Massachusetts Eye and Ear and Department of Ophthalmology at Harvard Medical School, Boston, MA, USA"},{"name":"Department of Ophthalmology, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petr","family":"Baranov","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, 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